1-methyl-2-[N-[4-(N-n-hexyloxycarbonylamidino)phenyl]aminomethyl]benzimidazole-5-yl-carboxylicacid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)amide is commonly known as Dabigatran etexilate. Dabigatran is an anticoagulant from the class of the direct thrombin inhibitors developed by Boehringer Ingelheim and is used for the treatment of thrombosis, cardiovascular diseases, and the like. Dabigatran etexilate mesylate was approved in both US and Europe and commercially available under the brand name Pradaxa.
Dabigatran etexilate and process for its preparation was first disclosed in WO 98/37075. The disclosed process involves the reaction of ethyl 3-(3-amino-4-(methylamino)-N-(pyridin-2-yl)benzamido)propanoate with 2-(4-cyanophenylamino) acetic acid in the presence of N,N-carbonyldiimidazole in tetrahydrofuran to provide ethyl 3-(2-((4-cyanophenylamino)methyl)-1-methyl-N-(pyridin-2-yl)-1H-benzo[d]imidazole-5-carboxamido)propanoate, which is further converted into 1-methyl-2-[N-[4-amidinophenyl]aminomethyl]benzimidazol-5-ylcarboxylicacid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)amide hydrochloride by reacting with ammonium carbonate in ethanol, followed by treating with ethanolic hydrochloric acid. The obtained compound was reacted with n-hexyl chloroformate in presence of potassium carbonate in tetrahydrofuran/water provides Dabigatran etexilate and further conversion into its mesylate salt was not disclosed. The purity of Dabigatran etexilate prepared as per the disclosed process is not satisfactory, and also the said process involves chromatographic purification which is expensive and difficult to implement in the large scale. Hence the said process is not suitable for commercial scale up.
Moreover, the said process proceeds through the 1-methyl-2-[N-[4-amidinophenyl]aminomethyl]benzimidazol-5-ylcarboxylicacid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)amide hydrochloride (herein after referred as “Dabigatran hydrochloride”), which degrades to form impurities and resulting in the formation of Dabigatran etexilate with low purity. In view of intrinsic fragility of Dabigatran hydrochloride, there is a need in the art to develop a novel salt form of 1-methyl-2-[N-[4-amidinophenyl]aminomethyl]benzimidazol-5-ylcarboxylicacid-N-(2-pyridyl)-N-(2-ethoxycarbonyl ethyl)amide, which enhances the purity of the final compound.
The prior reported processes disclosed in WO2012004396 and WO2008095928 A1 involves the usage of inorganic salts like hydrochloride and hydrobromide salts of ethyl 3-(2-((4-cyanophenylamino)methyl)-1-methyl-N-(pyridin-2-yl)-1H-benzo[d]imidazole-5-carboxamido) propanoate (herein after referred as “cyano intermediate”) and ethyl 3-(2-((4-carbamimidoyl phenylamino)methyl)-1-methyl-N-(pyridin-2-yl)-1H-benzo[d]imidazole-5-carboxamido) propanoate (herein after referred as “amidino intermediate”). The inorganic acid addition salts are less stable when compared to the organic acid addition salts and also the process for the preparation of organic acid addition salts is very much easy when compared to inorganic acid addition salt. Inorganic acid addition salts of amidine intermediate seem to be hygroscopic in nature. Therefore, organic acid addition salts are always preferable to synthesize stable salts which in-turn enhances the purity of the final compound.
The oxalate salt of cyano intermediate was disclosed in WO2009111997. However as on date, there is no other organic acid addition salts of cyano intermediate were reported in the prior art for preparing pure Dabigatran etexilate. Henceforth, there is a need to develop a novel organic acid addition salt of cyano intermediate compound which is very much efficient when compared to its corresponding oxalate salt and that result in the formation of final compound with high purity and yield.
The process disclosed in WO 98/37075 also involves the reduction of ethyl 3-(4-(methylamino)-3-nitro-N-(pyridin-2-yl)benzamido)propanoate (herein after referred as “nitro compound”) using Pd—C in a mixture of dichloromethane and methanol under hydrogen pressure to provide ethyl 3-(3-amino-4-(methylamino)-N-(pyridin-2-yl)benzamido)propanoate (herein after referred as “diamine compound”).
The reduction of nitro compound through catalytic hydrogenation in the presence of tertiary amine under hydrogen pressure was also disclosed in WO2009153214; and in presence of inorganic base under hydrogen pressure was also disclosed in WO2012004397.
However, most of the prior art processes proceed through catalytic hydrogenation which involves the pressure reactions. Handlings of these pressure reactions are not suitable for the large scale process. Therefore, there is a significant need in the art to provide a simple reduction process which avoids the difficulties associated with catalytic hydrogenation.
JMC, 2002, 45(9), 1757-1766 disclosed a process for the preparation of ethyl 3-(3-amino-4-(methylamino)-N-(pyridin-2-yl)benzamido)propanoate starting from 4-(methylamino)-3-nitrobenzoic acid. The disclosed process involves the conversion of 4-(methylamino)-3-nitrobenzoic acid into its acid chloride using thionyl chloride and the obtained compound was reacted with ethyl 3-(pyridin-2-ylamino)propanoate to provide nitro compound, followed by catalytic reduction using Pd—C to provide diamine compound.
However, particularly in large scale synthesis the reduction reaction occasionally stops due to catalyst poisoning which leads to incomplete reaction and requires additional catalyst to complete the reaction. Moreover the sulfur impurities which are present in nitro compound formed due to the reaction with thionyl chloride in the previous stages of the synthesis of diamine compound are strongly influence the reaction time, quality and catalyst consumption in the manufacturing process.
Surprisingly, the problem associated with the catalytic hydrogenation and catalyst poisoning is solved by the present invention by adopting a suitable reducing agent such as Fe-acetic acid and Fe-hydrochloric acid.
The crystalline forms-I, II, V and VI of Dabigatran etexilate oxalate were disclosed in WO2008043759 and WO2011110876.
The crystalline forms-III, IV and V of Dabigatran etexilate fumarate were disclosed in WO2008043759 and WO2011110876.
Various different salts for Dabigatran etexilate and their polymorphs were reported in WO98/37075, WO03074056, WO2005028468, WO2006114415, WO2008043759, WO2011110876, WO2012027543 and WO2012044595.
The process for the preparation of crystalline form-I of Dabigatran etexilate mesylate was described in WO2005028468 and WO2012027543.